Narcolepsy is a disabling and prevalent sleep disorder affecting 0.05-0.1 percent of the general population. Predisposition to human narcolepsy involves both genetic and environmental factors. Previous studies have shown that one of the genetic susceptibility factors involved is the Human Leukocyte (HLA) allele DQB1*0602. This allele however only accounts for a small portion of the overall genetic predisposition. (1) The first aim of this competing continuation application will be to refine our current understanding of HLA associations in narcolepsy. Preliminary data suggest that multiple HLA alleles as opposed to a single allele (e.g. DQB1*0602) have significant effects on disease predisposition. These data will be confirmed and the work will be extended to study HLA complex loci other than HLA-DQ. We anticipate that the results of this study will facilitate the use of HLA typing as a diagnostic tool and will allow us to estimate the contribution of the entire HLA complex (as opposed to a single HLA allele) to narcolepsy susceptibility. (2) A second aim will be to study genetic markers syntenic to the canine narcolepsy gene locus using previously identified multiplex families and singleton families. (3) Candidate genes in the area of immunology and neurochemistry will also be studied using an association-based design as part of the third specific aim. We anticipate that this proposal will allow us to identify novel narcolepsy genetic factors, some of which might also be fundamentally involved in sleep regulation.